Neutralizing monoclonal antibodies for COVID-19 treatment and prevention

The SARS-CoV-2 pandemic has caused unprecedented global health and economic crises. Several vaccine approaches and repurposed drugs are currently under evaluation for safety and efficacy. However, none of them have been approved for COVID-19 yet. Meanwhile, several nMAbs targeting SARS-CoV-2 spike glycoprotein are in different stages of development and clinical testing. Preclinical studies have shown that cocktails of potent nMAbs targeting the receptor binding site of SARS-CoV-2, as well as broad-nMAbs targeting conserved regions within the virus spike, might be effective for the treatment and prophylaxis of COVID-19. Currently, several clinical trials have started to test safety, tolerability, PKs and efficacy of these nMAbs. One paramount limitation for the use of nMAbs in clinical settings is the production of large amounts of MAbs and the high costs related to it. Cooperation among public and private institutions coupled with speed of development, rapid safety evaluation and efficacy, and early planning for scale-up and manufacture will be critical for the control of COVID-19 pandemicFil: Jaworski, Juan Pablo. Instituto Nacional de Tecnologia Agropecuaria. Centro de Investigacion En Ciencias Veterinarias y Agronomicas. Instituto de Virologia E Innovaciones Tecnologicas. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Pque. Centenario. Instituto de Virologia E Innovaciones Tecnologicas.; Argentin

Nuevas estrategias para el control y la prevención de la infección por HIV

Since its first isolation in 1983, the human immunodeficiency virus (HIV) has infected over 77 million people and only one patient from whom the virus was completely removed from the body was documented. A recent second case was reported that remains to be confirmed. Antiretroviral therapy (ART) manages to control blood viral replication and, consequently, to restore −at least partially− the functions of the immune system with a notable reduction of the morbidity and mortality associated with HIV infection. However, given the difficulty in eliminating the virus from the body, treatment has to be given for life. This long-term exposure to antiretroviral drugs implies the risk of generating intolerance, toxic effects, gaps in adherence and selection of resistance mutations. Another limitation is the high cost of treating 37 million persons living with HIV, most of whom are living in resource-limited countries and relying on international aid initiatives. Having these challenges in mind, there is general agreement that new approaches for preventing and treating HIV infection are needed to control the epidemic, while efforts on vaccine development continue. In this regard, new generation broadly neutralising monoclonal antibodies (bnMAbs) against the HIV envelope protein can prevent virus acquisition, reduce viremia, enhance immunity, and induce the killing of infected cells in animal models of HIV infection. Most importantly, some clinical trials have shown that bnMAbs could effectively decrease viremia and delay viral rebound in people chronically infected with HIV.Desde su primer aislamiento en 1983, el virus de la inmunodeficiencia humana (HIV) ha infectado a más de 77 millones de personas y solo se ha documentado un caso en el cual el virus fue removido completamente del organismo; aún resta confirmar un segundo caso informado recientemente. El tratamiento antirretroviral logra controlar la replicación viral en el plasma y en consecuencia recuperar (al menos parcialmente) la actividad del sistema inmune, con una notable reducción de la morbilidad y la mortalidad asociadas a la infección por HIV. Sin embargo, ante la dificultad para eliminar completamente el virus del organismo, es necesario continuar el tratamiento de por vida. Esto implica la exposición a largo plazo a drogas antirretrovirales con riesgo de generar intolerancia, efectos tóxicos, brechas en la adherencia y selección de mutantes resistentes. Otro aspecto a considerar es la carga económica que implica tratar a 37 millones de personas infectadas con HIV, la mayoría de ellas en países que solo pueden afrontar esos costos con ayuda internacional. Por ello, hasta tanto se disponga de una vacuna capaz de prevenir la infección de todas las formas circulantes del HIV, es necesario desarrollar nuevas herramientas terapéuticas capaces de complementar y potenciar los efectos del tratamiento antirretroviral. Diversos ensayos preclínicos sugieren que la administración pasiva de anticuerpos monoclonales dirigidos contra la glicoproteína de envoltura viral podría prevenir la infección, reducir la carga viral, estimular la respuesta inmune y favorecer la eliminación de células infectadas con HIV.Fil: Jaworski, Juan Pablo. Instituto Nacional de Tecnologia Agropecuaria. Centro de Investigacion En Ciencias Veterinarias y Agronomicas. Instituto de Virologia E Innovaciones Tecnologicas. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Pque. Centenario. Instituto de Virologia E Innovaciones Tecnologicas.; ArgentinaFil: Frola, Claudia. Fundación Huésped; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Cahn, Pedro. Fundación Huésped; Argentin

Neutralizing monoclonal antibodies to fight HIV-1 : on the threshold of success

Anti-human immunodeficiency virus type-1 (anti-HIV-1) neutralizing monoclonal antibodies are broadening the spectrum of pre- and post-exposure treatment against HIV-1. A better understanding of how these antibodies develop and interact with particular regions of the viral envelope protein is guiding a more rational structure-based immunogen design. The aim of this article is to review the most recent advances in the field, from the development of these particular antibodies during natural HIV-1 infection, to their role preventing infection, boosting endogenous immune responses and clearing both free viral particles and persistently infected cells.Inst.de VirologíaFil: Jaworski, Juan Pablo. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Vendrell, Alejandrina. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Chiavenna, Sebastián Matias. Ferrer Advanced Biotherapeutics, Ferrer Internacional; Españ

Regulation of Expression and Latency in BLV and HTLV

Human T-lymphotrophic virus type 1 (HTLV-1) and Bovine leukemia virus (BLV) belong to the Deltaretrovirus genus. HTLV-1 is the etiologic agent of the highly aggressive and currently incurable cancer adult T-cell leukemia (ATL) and a neurological disease HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). BLV causes neoplastic proliferation of B cells in cattle: enzootic bovine leucosis (EBL). Despite the severity of these conditions, infection by HTLV-1 and BLV appear in most cases clinically asymptomatic. These viruses can undergo latency in their hosts. The silencing of proviral gene expression and maintenance of latency are central for the establishment of persistent infection, as well as for pathogenesis in vivo. In this review, we will present the mechanisms that control proviral activation and retroviral latency in deltaretroviruses, in comparison with other exogenous retroviruses. The 50 long terminal repeats (50-LTRs) play a main role in controlling viral gene expression. While the regulation of transcription initiation is a major mechanism of silencing, we discuss topics that include (i) the epigenetic control of the provirus, (ii) the cis-elements present in the LTR, (iii) enhancers with cell-type specific regulatory functions, (iv) the role of virally-encoded transactivator proteins, (v) the role of repressors in transcription and silencing, (vi) the effect of hormonal signaling, (vii) implications of LTR variability on transcription and latency, and (viii) the regulatory role of non-coding RNAs. Finally, we discuss how a better understanding of these mechanisms may allow for the development of more effective treatments against Deltaretroviruses.Fil: Pluta, Aneta. National Veterinary Research Institute; PoloniaFil: Jaworski, Juan Pablo. Instituto Nacional de Tecnologia Agropecuaria. Centro de Investigacion En Ciencias Veterinarias y Agronomicas. Instituto de Virologia E Innovaciones Tecnologicas. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Pque. Centenario. Instituto de Virologia E Innovaciones Tecnologicas.; ArgentinaFil: Douville, Renée N.. University of Manitoba; Canad

Balance between retroviral latency and transcription : based on HIV model

The representative of the Lentivirus genus is the human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS). To date, there is no cure for AIDS because of the existence of the HIV-1 reservoir. HIV-1 infection can persist for decades despite effective antiretroviral therapy (ART), due to the persistence of infectious latent viruses in long-lived resting memory CD4+ T cells, macrophages, monocytes, microglial cells, and other cell types. However, the biology of HIV-1 latency remains incompletely understood. Retroviral long terminal repeat region (LTR) plays an indispensable role in controlling viral gene expression. Regulation of the transcription initiation plays a crucial role in establishing and maintaining a retrovirus latency. Whether and how retroviruses establish latency and reactivate remains unclear. In this article, we describe what is known about the regulation of LTR-driven transcription in HIV-1, that is, the cis-elements present in the LTR, the role of LTR transcription factor binding sites in LTR-driven transcription, the role of HIV-1-encoded transactivator protein, hormonal effects on virus transcription, impact of LTR variability on transcription, and epigenetic control of retrovirus LTR. Finally, we focus on a novel clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/dCas9)-based strategy for HIV-1 reservoir purging.Instituto de VirologíaFil: Pluta, Aneta. National Veterinary Research Institute. Department of Biochemistry; PoloniaFil: Jaworski, Juan Pablo. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; ArgentinaFil: Jaworski, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Tecnológicas; ArgentinaFil: Cortés-Rubio, César N. National Institute of Respiratory Diseases. Centre for Research in Infectious Diseases; Méxic

Spontaneous virus reactivation in cattle chronically infected with bovine leukemia virus

Background: The absence of virus expression during the chronic stage of bovine leukemia virus (BLV) infection and its reactivation upon ex vivo culture has become a long-lived Dogma. During the chronic stage of BLV infection the immune response limits viral replication and the mitotic division of latently infected cells, carrying BLV provirus, allows viral expansion and disease progression towards a lymphoproliferative disorder. Several stressor factors have been associated with animal production and handling. As natural mediator of stress, glucocorticoids are strong immunosuppressive agents; moreover, they can bind long-terminal repeat region of retroviruses and induce viral expression. In the present study, we present a case report describing the spontaneous reactivation of BLV infection in naturally infected cattle. Case presentation: In order to investigate if virus reactivation occurred in vivo during the course of BLV infection, we followed up for 328 days one Holstein cow (> 3 years) chronically infected with BLV which presented high-proviral loads. This animal was neither lactating nor pregnant. Furthermore, we investigated if a stressor stimulus, in this case the administration of a synthetic glucocorticoid (dexamethasone), could impact the course of BLV infection in three additional cattle. For the first time, we observed a high level of BLV transcripts in a total of four cattle chronically infected with BLV. The detection of viral transcripts corresponding to pol gene strongly suggests virus reactivation in these animals. Interestingly, this simultaneous virus reactivation was unrelated to dexamethasone treatment. Conclusions: We reported for the first time spontaneous and high level of BLV transcriptional activation in cattle chronically infected with BLV. Although virus reactivation was unrelated to dexamethasone treatment, other stressor stimuli might have influenced this outcome. Future studies will be necessary to understand these observations, since the spontaneous virus reactivation presented here might have implications on BLV pathogenesis and transmission.Instituto de VirologíaFil: Jaworski, Juan Pablo. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Tecnológicas; ArgentinaFil: Petersen, Marcos Iván. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Tecnológicas; ArgentinaFil: Carignano, Hugo. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Tecnológicas; ArgentinaFil: Trono, Karina Gabriela. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Tecnológicas; Argentin

Quantification of bovine leukemia virus proviral DNA using a low-cost real-time polymerase chain reaction

The detection of bovine leukemia virus (BLV) proviral DNA is an important tool to address whether an animal is infected with BLV. Compared with serological assays, real-time PCR accounts for greater sensitivity and can serve as a confirmatory test for the clarification of inconclusive or discordant serological test results. However, the high cost related to real-time PCR assays has limited their systematic inclusion in BLV surveillance and eradication programs. The aim of the present study was to validate a low-cost quantitative real-time PCR. Interestingly, by using SYBR Green detection dye, we were able to reduce the cost of a single reaction by a factor of 5 compared with most common assays based on the use of fluorogenic probes (i.e., TaqMan technology). This approach allowed a highly sensitive and specific detection and quantification of BLV proviral DNA from purified peripheral blood leukocytes and a milk matrix. Due to its simplicity and low cost, our in-house BLV SYBR quantitative real-time PCR might be used either as a screening or as a confirmatory test in BLV control programs.Fil: Petersen Cruceño, Marcos Iván. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alvarez, Irene. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Trono, Karina Gabriela. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Jaworski, Juan Pablo. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Nueva terapia con anticuerpos monoclonales permitiría eliminar el reservorio del virus de la inmunodeficiencia humana (HIV-1)

Fil: Jaworski, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria; Argentin

Monoclonal Antibody for Patients with Covid-19

The ACTIV-3/TICO LY-CoV555 Study Group (Dec. 22)1 hypothesized that low penetration of the antibody into the infected lungs might explain the lack of benefit of bamlanivimab (LY-CoV555) in hospitalized patients with coronavirus disease 2019 (Covid-19). However, we previously measured transudation of human immunodeficiency virus type 1 (HIV-1) monoclonal antibodies (VRC07-523 and PGT121) into tissues of 1-month-old rhesus macaques as part of a study to assess the effectiveness of monoclonal antibodies as postexposure prophylaxis.2 We detected high concentrations of passively transferred antibodies in the lungs of the two macaques (250 ng per milliliter in one and 285 ng per milliliter in the other) after subcutaneous administration of 10 mg per kilogram of body weight of monoclonal antibody cocktail. The concentration of antibody in the lungs was higher than the mean concentration detected in 26 other tissues (184 ng per milliliter); monoclonal antibody biodistribution was not affected by the virus in challenged animals.Our observations suggest that the rapid selection of neutralization-resistant variants, rather than biodistribution, might have undermined the efficacy of bamlanivimab in this trial. This hypothesis is supported by recent data provided by Regeneron about the preliminary efficacy of the combination of casirivimab and imdevimab in reducing the risk of death or mechanical ventilation in hospitalized patients with Covid-19.Fil: Jaworski, Juan Pablo. Instituto Nacional de Tecnologia Agropecuaria. Centro de Investigacion En Ciencias Veterinarias y Agronomicas. Instituto de Virologia E Innovaciones Tecnologicas. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Pque. Centenario. Instituto de Virologia E Innovaciones Tecnologicas.; Argentin